C/EBP Homologous Binding Protein (CHOP) Underlies Neural Injury in Sleep Apnea Model

Sleep. 2013 Apr 1;36(4):481-92. doi: 10.5665/sleep.2528.

Abstract

Study objectives: Obstructive sleep apnea (OSA) is associated with cognitive impairment and neuronal injury. Long-term exposure to intermittent hypoxia (LTIH) in rodents, modeling the oxygenation patterns in sleep apnea, results in NADPH oxidase 2 (Nox2) oxidative injury to many neuronal populations. Brainstem motoneurons susceptible to LTIH injury show uncompensated endoplasmic reticulum stress responses with increased (CCAAT/enhancer binding protein homologous protein (CHOP). We hypothesized that CHOP underlies LTIH oxidative injury. In this series of studies, we first determined whether CHOP is upregulated in other brain regions susceptible to LTIH oxidative Nox2 injury and then determined whether CHOP plays an adaptive or injurious role in the LTIH response. To integrate these findings with previous studies examining LTIH neural injury, we examined the role of CHOP in Nox2, hypoxia-inducible factor-1α (HIF-1α) responses, oxidative injury and apoptosis, and neuron loss.

Design: Within/between mice subjects.

Setting: Laboratory setting. PARTICIPANTSSUBJECTS: CHOP null and wild-type adult male mice.

Interventions: LTIH or sham LTIH.

Measurements and main results: Relative to wild-type mice, CHOP-/- mice conferred resistance to oxidative stress (superoxide production/ carbonyl proteins) in brain regions examined: cortex, hippocampus, and motor nuclei. CHOP deletion prevented LTIH upregulation of Nox2 and HIF-1α in the hippocampus, cortex, and brainstem motoneurons and protected mice from neuronal apoptosis and motoneuron loss.

Conclusions: Endogenous CHOP is necessary for LTIH-induced HIF-1α, Nox2 upregulation, and oxidative stress; CHOP influences LTIH-induced apoptosis in neurons and loss of neurons. Findings support the concept that minimizing CHOP may provide neuroprotection in OSA.

Keywords: GADD153 and gp91phox; Hypoxia; PERK; reoxygenation; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis
  • Blotting, Western / methods
  • Brain / metabolism*
  • Brain / physiopathology*
  • Disease Models, Animal
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Neurons / metabolism*
  • NADPH Oxidases / metabolism
  • Oxidative Stress
  • Real-Time Polymerase Chain Reaction / methods
  • Sleep Apnea Syndromes / metabolism*
  • Sleep Apnea Syndromes / physiopathology*
  • Transcription Factor CHOP / metabolism*

Substances

  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transcription Factor CHOP
  • NADPH Oxidases